Doberman pinschers present autoimmunity associated with functional autoantibodies: A model to study the autoimmune background of human dilated cardiomyopathy.

BACKGROUND

Autoimmunity associated with autoantibodies against the β1-adrenergic receptor (β1-AAB) is increasingly accepted as the driver of human dilated cardiomyopathy (DCM). Unfortunately, there is a lack of animal models to extend the knowledge about β1-AAB autoimmunity in DCM and to develop appropriate treatment strategies.

OBJECTIVES

To introduce an animal model, we investigated the β1-AAB associated autoimmunity in Doberman Pinscher (DP) with dilated cardiomyopathy, which has similarities to human DCM.

MATERIALS AND METHODS

Eighty-seven DP with cardiomyopathy in terms of pathological ECG and echocardiography (DoCM) and 31 dogs (at enrollment) without DoCM (controls) were analyzed for serum activity of β1-AAB with a bioassay that records the chronotropic response of spontaneously beating cultured neonatal rat cardiomyocytes to the DP's IgG. To locate the receptor binding site of β1-AAB and the autoantibody's sensitivity to inhibition, competing experiments with related blockers were performed with the bioassay. In controls that developed DoCM during follow-up, β1-AAB were analyzed during progress.

RESULTS

Fifty-nine (67.8%) DoCM dogs and 19 (61.3%) controls were β1-AAB positive. Of the controls that developed DoCM, 8 were β1-AAB positive (p = 0.044 vs. dogs remaining in the control group); their β1-AAB activity increased with the cardiomyopathy progress (p<0.02). To supplement DoCM group with the 9 animals which developed cardiomyopathy in the follow up, a more pronounced β1-AAB positivity became visible in the DoCM group (p = 0.066). Total and cardiac mortality were higher in β1-AAB positive DP (p = 0.002; p = 0037). The dogs' β1-AAB recognized a specific epitope on the second extracellular receptor and were sensitive to inhibition by drugs already successfully tested to inhibit the corresponding human autoantibody.

CONCLUSIONS

Doberman Pinschers presented β1-AAB associated autoimmunity, similar as in the pathogenesis of human DCM. Consequently, DP could compensate the lack of animal models for the investigation of β1-AAB autoimmunity in human DCM.

Déclaration de conflit d'intérêts

We have read the journal’s policy and the authors of this manuscript have the following competing interests: The authors declare that the study was not funded by any public, commercial or private funds. Gerd Wallukat, Niels-Peter Becker, Katrin Wenzel, Johannes Müller and Ingolf Schimke as employees and shareholder (GW, JM, IS) of Berlin Cures GmbH declare that this does not alter our adherence to PLOS ONE policies on sharing data and materials. Berlin Cures GmbH only provided support in the form of salaries and research materials but did not have any additional role in the study design, data collection, analysis and statistical evaluation, decision to publish or preparation of the manuscript. Anna Fritscher and Gerhard Wess declare that they have no conflict of interest. Berlin Cures GmbH, a spin-off company, founded in September 2014 for the commercial exploitation of patents held by Charité – Universitätsmedizin Berlin and Max-Delbrück-Center Berlin, Germany.